The tetracycline compound, 7-dimethylamino-6-deoxy-6-demethyltetracycline, and its non-toxic acid addition salts are widely used in therapy primarily for their antimicrobial effects. Commonly assigned Boothe et al, U.S. Pat. No. 3,148,212, and Pesti et al, U.S. Pat. No. 3,226,436, describe the preparation of minocycline. Although the compounds have achieved widespread use in oral dosage forms, they have several drawbacks.
The minimum therapeutically effective blood serum or plasma concentration level of minocycline in a human subject varies according to the organism causing the infection. The concentration is determined in vivo by clinical evaluation and in vitro by microbiological assays. Currently, the minimum therapeutically effective concentration is believed to be in the range of from about 0.1 to about 1.0 mcg of minocycline/ml of serum.
Organisms currently known to be susceptible to minocycline therapy include a wide range of gram-negative and gram-positive bacteria including, but not limited to agents of rickettsiae (Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsial pox, tick fevers); Mycoplasma pneumonias (PPLO, Eaton agent); agents of psittacosis and ornithosis; agents of lymphogranuloma venereum and granuloma inguinale; the spirochetal agent of relapsing fever (Borrelia recurrentis); the agent of Lyme disease (Borrelia burgdorfeni), the agents of acne (Propionibacterium Corynebacterium acnes); the microorganisms Haemophilus ducreyi(chancroid), Yersinia pestis and Francisella tularensis, formerly Pasteurella pestis and Pasteurella tularensis, Bartonella bacilliformis, Bacteroides species, Vibrio cormna and Vibrio fetus, Brucella species, Escherichia coli, Enterbacter aerogenes (formerly Aerobacter aerogenes), Shigella species, Mima species, Herellea species, Haemophilus influenzas (respiratory infections), Klebsiella species (respiratory and urinary infections), many Streptococcus species including strains of Streptococcus pyogenes and Streptococcus faecalis, Streptococcus pneumonias, Staphylococcus aureus (skin and soft tissue infections), Neisseria gonorrhoeae, Neisseria meningitidis, Treponema pallidum and Treponema pertenue (syphilis and yaws), Listeria monocytogenes Clostridium species, Bacillus anthracis, Fusobacterium fusiforme (Vincent's infection), Actinomyces species; and in the treatment of acute intestinal amebiasis and inclusion conjunctivitis. Physician's Desk Reference, 1987, Medical Economics Company, Oradell, N.J. (PDR 43rd Ed.).
Recent discovery shows that minocycline is absorbed at different rates in different portions of the gastrointestinal tract. Intubation studies in human patients have demonstrated that bioavailability of minocycline in the gastrointestinal tract, based upon 100 percent absorption in the stomach, is 106 percent in the duodenum, 80 percent in the jejunum and 58 percent in the ileum, indicating that minocycline demonstrates reduced absorption in the lower gastrointestinal tract.
The human stomach empties in about one hour in a fasting subject and in about one to about four hours with food. The half life of minocycline when taken without food is approximately 10 hours. When taken with food, the half life is extended to approximately 14 to 16 hours.
It has not been possible to achieve a once-a-day therapeutic blood level of minocycline using only delayed release granules of minocycline with or without food ingestion. Traditional pharmaceutical forms containing minocycline require frequent ingestion of multiple doses per day resulting in wide variations in serum concentration throughout the course of treatment and in poor patient compliance and traditional delayed release forms containing minocycline are incompletely absorbed in the gastrointestinal tract. This indicates a need for a custom designed once-a-day delivery system for minocycline to provide optimal therapeutic effect and patient compliance.
Lederle Laboratories has recently offered for use by the medical profession, capsules under the trademark MINOCIN.RTM. containing specially coated pellets of minocycline hydrochloride for oral administration. See, PDR 44th Ed. (Pages 1168-1170). In contrast to tablets and powder-filled capsules, pelletized minocycline hydrochloride provides virtually complete absorption with dairy products and food. The capsules, however, are not intended to provide a once-a-day dosage form.
Valorose et al, U.S. Pat. No. 4,837,030, disclose hard gelatin or soft gelatin capsules filled with minocycline comprising spherical granules. This patent teaches controlled release formulations of minocycline wherein the rate of release in the stomach and intestines is controlled. The delivery system may be comprised of coated or uncoated spheres. The medicament may be within the sphere or in the coating. Valorose further teaches coating the spherical granules with hydroxypropyl methylcellulose and hydroxypropyl methylcellulose phthalate. The controlled release in Valorose, however, is not taught to be prolonged up to 24 hours.
Shepard, U.S. Pat. No. 3,080,294, discloses a sustained release pharmaceutical tablet comprising an inner core coated with multiple layers of an active medicament mixture, each layer releasing a portion of active medicament as it is successively dissolved. Such layers are not pH adapted, however. Shepard further teaches sustained release pharmaceutical formulations wherein medicament coated pellets and uncoated medicament pellets maintain therapeutic blood concentration levels for prolonged periods of time. The medicament may be in the coating or in the core. Shepard also teaches the use of coatings comprised of cellulose esters and pH sensitive polymer coatings. As explained in example 4 of Shepard, the dosage forms are formulated so that a perdetermined amount of active ingredient may be released in the stomach (pH less than 3.9) and a predetermined amount may be released in the intestines (pH 4-7.5) approximately.
In copending, commonly assigned U.S. patent application Ser. No. 07/410,708, filed Sep. 21, 1989, now abandoned, it is disclosed that a specific minocycline composition can be formulated to provide at least minimum therapeutic serum levels of the minocycline in a human subject for about 24 hours through once-a-day two pulse administration systems, comprising an initial loading component providing the first pulse which is absorbed up to 100 percent in the stomach and a secondary loading component providing the second pulse which is absorbed up to 100 percent in the duodenum and the upper part of the small intestine. Working examples are provided which contain a minor proportion of the initial loading component and a major proportion of the secondary loading component. In addition, the working examples include procedures to coat granules comprising the secondary loading component with a blended polymer coating composition to give them slow release characteristics. The formulations of the copending application are taught to be processable into capsule oral dosage unit forms. In vivo data with a preferred embodiment of the copending application comprising capsules containing 46% of the total dose in the form of uncoated quick-release pellets and 54% in the form of single polymer (hydroxypropyl methylcellulose phthalate)-coated slow-release pellets showed good bioavailability over 24 hours after a single administration, approaching the achieved with two divided doses of conventional minocycline tablets.
It has now been discovered that bioavailability can be even more improved by increasing the ratio of quick release initial loading pellets to slow release secondary loading coated pellets and by using a modified coating composition for the latter. Thus, for example, the bioavailability can be improved by greater than 10% by using a major proportion, e.g., 60% of the quick-release granules and a minor proportion, e.g., of the slow-release granules and providing the latter with a coating comprising a small amount of water-soluble polymer in the pH-sensitive polymer previously used alone. In addition, in multidose studies, the mixed pellet dosage forms of the present invention exhibit a surprising retention of bioavailability after ingestion of food in comparison with tablets employed in the present state of the art. Data are presented hereinafter which show that fed subjects had an absorption of 100% of that of the fasted subjects with the dosage forms of this invention but only 90.6% with the prior art tablets.
These results are surprising because just the opposite would be expected. An early release of most of the minocycline in the stomach should reduce the long time effectiveness, but, as will be seen, single dose bioavailability versus the reference tablet given twice a day is increased from 79% to 89%, and the latter is unaffected by food intake as is shown in the multidose studies.